US 2004/0110768 A1Published application

Bombesin receptor antagonists

OwnerMichael Higginbottom, Martyn Clive Pritchard +1inventors

InventorsMichael Higginbottom, Martyn Clive Pritchard, Herman Thijs Stock

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Abstract

Bombesin receptor antagonists are provided which are compounds of formula (I) or pharmaceutically acceptable salts thereof: 1 wherein j, k, l, m, n, q, r, Ar, Ar1, R1, R2, R3, R4, R5, R6 and X are as defined in the description. The compounds of the invention have an affinity for the BB1 receptor and some of them also have affinity for the BB2 receptor. Accordingly they may be useful for the diagnosis, prevention, or treatment of male and female sexual dysfunction. They can also be used in the diagnosis, prevention or treatment of anxiety and panic disorders, social phobia, depression, psychoses, sleeping disorders, memory impairment, pulmonary hypertension, lung repair and lung development disorders, cancer including prostate cancer and pancreatic cancer, hepatic porphyria, gastrointestinal secretory disturbances, gastrointestinal disorders including colitis, Crohn's disease and inflammatory bowel disease, emesis, anorexia, pain, seasonal affective disorders, feeding disorders or pruritus.

Claims24

Dependent claims

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

49
wherein:
j is 0, 1 or 2;
k is 0 or 1;
l is 0, 1, 2, or 3;
m is 0 or 1;
n is 0, 1 or 2;
q is 0 or 1;
r is 0 or 1;
when r is 0, Ar is replaced by hydrogen;
Ar is phenyl, pyridyl, pyrimidyl, thienyl, furyl, imidazolyl, pyrrolyl or thiazolyl each unsubstituted or substituted by from 1 to 3 substituents selected from acetyl, alkoxy, alkyl, amino, cyano, halo, hydroxy, nitro, sulfonamido, sulfonyl, —CF3, —OCF3, —CO2H, —CH2CN, —SO2CF3, —CH2CO2H and —(CH2)5NR7R8 wherein s is 0, 1, 2 or 3 and R7 and R8 are each independently selected from H, straight or branched alkyl of up to 6 carbon atoms, or R7 and R8, together with the nitrogen atom to which they are linked, can form a 5- to 7-membered aliphatic ring which may contain 1 or 2 oxygen atoms;
R1 is hydrogen, straight or branched alkyl of up to 6 carbon atoms or cycloalkyl of between 5 and 7 carbon atoms which may contain 1 or 2 nitrogen or oxygen atoms;
R6 is hydrogen, methyl or forms with R1 an aliphatic ring of from 3 to 7 atoms which can contain an oxygen or nitrogen atom, or together with R1 is a carbonyl group;
Ar1 is independently selected from Ar or is indolyl or pyridyl-N-oxide;
R3, R4, and R5 are each independently selected from hydrogen and lower alkyl;
R2 is independently selected from Ar or is hydrogen, hydroxy, alkoxy, —NMe2, —CONR9R10 wherein R9 and R10 are each independently selected from hydrogen, straight or branched alkyl of up to 6 carbon atoms, or R9 and R10 together with the nitrogen atom to which they are linked can form a 5- to 7-membered aliphatic ring which may contain 1 or 2 oxygen or nitrogen atoms, or R2 is
50
wherein p is 0, 1 or 2 and Ar2 is phenyl or pyridyl;
X is a divalent radical derived from any of the following:
51 52
where the ring nitrogen atoms may have lower alkyl groups attached thereto, R11, R12 are independently selected from H, halogen, hydroxy, alkoxy, acetyl, nitro, cyano, amino, CF3 and (CH2)tNR13R14 wherein t can be 0 or 1, R13 and R14 are each independently selected from hydrogen, straight or branched alkyl of up to 6 carbon atoms or cycloalkyl of 5 to 7 carbon atoms, containing up to 2 oxygen or nitrogen atoms;
provided that, when Ar1 is indolyl, then
(i) r is 1 or q is 1, or
(ii) R6 forms with R1 an aliphatic ring of from 3 to 7 atoms which can contain an oxygen or nitrogen atom, or R6 together with R1 is a carbonyl group.

21 more elements

Any of the following compounds or a pharmaceutically acceptable salt thereof:

(S)-3-(1H-indol-3-yl)-N-(1-methoxymethyl-cyclohexylmethyl)-2-methyl-2-[4-(4-nitro-phenyl)-oxazol-2-ylamino]-propionamide;
(S)-3-(1H-indol-3-yl)-2-methyl-2-[4-(4-nitro-phenyl)-oxazol-2-ylamino]-N-(2-oxo-2-phenyl-ethyl)-propionamide;
(S)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-2-[4-(4-nitro-phenyl)-oxazol-2-ylamino]-3-phenyl-propionamide;
(S)-2-[4-(4-cyano-phenyl)-oxazol-2-ylamino]-3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-propionamide;
(S)-3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-2-(4-phenyl-oxazol-2-ylamino)-propionamide;
(S)-2-(4-ethyl-oxazol-2-ylamino)-3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-propionamide;
(S)-3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-2-[4-(4-nitro-phenyl)-thiazol-2-ylamino]-propionamide;
(S)-2-(benzooxazol-2-ylamino)-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-2-yl-cyclohexylmethyl)-propionamide;
(S)-3-(1H-indol-3-yl)-2-methyl-2-(pyridin-4-ylamino)-N-(1-pyridin-2-yl-cyclohexylmethyl)-propionamide;
(S)-3-(1H-indol-3-yl)-2-(isoquinol-4-ylamino)-2-methyl-N-(1-pyridin-2-yl-cyclohexylmethyl)-propionamide;
(S)-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-2-yl-cyclohexylmethyl)-2-(pyrimidin-5-ylamino)-propionamide;
(S)-2-(biphenyl-2-ylamino)-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-2-yl-cyclohexylmethyl)-propionamide;
(S)-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-2-yl-cyclohexylmethyl)-2-m-tolylamino-propionamide;
(S)-3-(1H-indol-3-yl)-2-methyl-2-(6-phenyl-pyridin-2-ylamino)-N-(1-pyridin-2-yl-cyclohexylmethyl)-propionamide;
(R)-3-phenyl-2-phenylamino-N-(1-pyridin-2-yl-cyclohexylmethyl)-propionamide;
(S)-3-(1H-indol-3-yl)-2-methyl-2-phenylethylamino-N-(1-pyridin-2-yl-cyclohexylmethyl)-propionamide;
(S)-2-[(benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-2-yl-cyclohexylmethyl)-propionamide, and
(S)-3-(1H-indol-3-yl)-2-methyl-2-(4-nitro-benzylamino)-N-(1-pyridin-2-yl-cyclohexylmethyl)-propionamide.

15 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/416,251Filed 4 Dec 2003
Priority: GB 0028146.917 Nov 2000
Published: 10 Jun 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification31 codes

C07D 213/40
Radicals substituted by singly-bound nitrogen atoms: acylated substituent nitrogen atom
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/08
Drugs for disorders of the alimentary tract or the digestive system: for nausea, cinetosis or vertigo; Antiemetics